US7642363B2 - Process for the preparation of 2-(6-substituted-1,3-dioxane-4-YL) acetic acid derivatives - Google Patents

Process for the preparation of 2-(6-substituted-1,3-dioxane-4-YL) acetic acid derivatives Download PDF

Info

Publication number
US7642363B2
US7642363B2 US11/053,090 US5309005A US7642363B2 US 7642363 B2 US7642363 B2 US 7642363B2 US 5309005 A US5309005 A US 5309005A US 7642363 B2 US7642363 B2 US 7642363B2
Authority
US
United States
Prior art keywords
compound
group
formula
substituted
dioxane
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime, expires
Application number
US11/053,090
Other versions
US20050148785A1 (en
Inventor
Jacob Hermanus Mattheus Hero Kooistra
Hubertus Josephus Marie Zeegers
Daniel Mink
Joannes Maria Cornelis Antonius Mulders
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca UK Ltd
Original Assignee
AstraZeneca UK Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by AstraZeneca UK Ltd filed Critical AstraZeneca UK Ltd
Priority to US11/053,090 priority Critical patent/US7642363B2/en
Publication of US20050148785A1 publication Critical patent/US20050148785A1/en
Priority to US12/625,156 priority patent/US7989643B2/en
Application granted granted Critical
Publication of US7642363B2 publication Critical patent/US7642363B2/en
Priority to US13/166,607 priority patent/US20110251406A1/en
Adjusted expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]

Definitions

  • the invention relates to a process for the preparation of a 2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivative of formula 1
  • R 1 , R 2 and R 3 each independently stand for an alkyl group with 1-3 carbon atoms, starting from a compound of formula 2
  • the invention also relates to the new compounds of formula 1, as well as salts and acids of formula 3 that can be obtained therefrom
  • R 1 and R 2 have the above-mentioned meanings and where Y stands for an alkaline (earth)metal or a substituted or non-substituted ammonium group or stands for hydrogen.
  • the 2-(6-substituted 1,3-dioxane-4-yl)-acetic acid derivative can be obtained selectively and in a high yield from the corresponding compound of formula (2), it being possible to prepare these products, which are relatively little stable, under mild conditions.
  • This is all the more interesting since this provides a simple route via the corresponding salt, the corresponding t-butyl ester, and the 2-hydroxymethyl-substituted compound as intermediates in the preparation of HMG-CoA reductase inhibitors.
  • the conversion proceeds (depending on the reaction conditions chosen) via an intermediary salt or ester, with the ring in the compound according to formula (2) being opened.
  • An added advantage of the process according to the invention is that both the starting compounds of formula (2) and the products of formula 3 are found to be crystalline compounds. This is advantageous in obtaining products with a (chemically and stereochemically) high purity. This is important in particular in view of the intended pharmaceutical application.
  • the (4R,6S)-2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivative is important. It can be prepared from the corresponding 6-substituted-2,4,6-trideoxy-D-erythrohexose.
  • the invention therefore, also relates to the starting compounds of formula 1, in particular where X ⁇ Cl, and to particles of such compounds. In particular more than 90 wt.
  • % of the particles has a length/diameter ratio between 1:1.5 and 1:6, preferably between 1:2 and 1:4.4 and a length of the particles between 0.05 and 2 mm, in particular between 0.1 and 1 mm.
  • the invention also relates to such particles.
  • the compound of formula II gives clear crystalline particles with a sharp melting point of 73-74° C.
  • the products of formula 3 derived from the (4R,6S)-2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivative of formula 1 can according to the invention be prepared with an enantiomeric excess (e.e.) of more than 95%, in particular more than 99.5%, and with a diastereomeric excess (d.e.) of more than 90%, in particular more than 99.5%.
  • an enantiomeric excess e.e.
  • d.e. diastereomeric excess
  • Suitable leaving groups X that can be applied in the process according to the invention are halogens, in particular Cl, Br or I; tosylate groups; mesylate groups; acyloxy groups, in particular acetoxy and benzoyloxy groups; an aryloxy-, in particular benzyloxy-, or a nitro-substituted benzene sulphonyl group.
  • Cl is preferably chosen as leaving group.
  • acetalization agents that can be applied in the process according to the invention are dialkoxypropane compounds, with the alkoxy groups each preferably having 1-3 carbon atoms, for instance 2,2-dimethoxypropane or 2,2-diethoxypropane; alkoxypropene, with the alkoxy group preferably having 1-3 carbon atoms, for instance 2-methoxypropene or 2-ethoxypropene. Most preferred is 2,2-dimethoxypropane. This can optionally be formed in situ from acetone and methanol, preferably with water being removed.
  • acid catalyst use can be made of the acid catalysts known for acetalization reactions, preferably non-nucleophilic strong acids, for example sulphonic acids, in particular p-toluene sulphonic acid, methane sulphonic acid of camphor sulphonic acid; inorganic acids with a non-nucleophilic anion, for example sulphuric acid, phosphoric acid: acid ion exchangers, for example DOWEX; or solid acids, for example the so-called heteropolyacids.
  • non-nucleophilic strong acids for example sulphonic acids, in particular p-toluene sulphonic acid, methane sulphonic acid of camphor sulphonic acid
  • inorganic acids with a non-nucleophilic anion for example sulphuric acid, phosphoric acid: acid ion exchangers, for example DOWEX
  • solid acids for example the so-called heteropolyacids.
  • the acetalization can be carried out without using a separate solvent; if desired the reaction can also be carried out in an organic solvent.
  • suitable organic solvents are ketones, in particular acetone, hydrocarbons, in particular aromatic hydrocarbons, for example toluene, chlorinated hydrocarbons, for example methylene chloride.
  • the temperature at which the acetalization reaction is carried out preferably lies between ⁇ 20° C. and 60° C., in particular between 0° C. and 30° C.
  • the acetalization reaction is preferably carried out under an inert atmosphere.
  • the molar ratio of acetalization agent to starting compound of formula (2) preferably lies between 1:1 and 20:1, in particular between 3:1 and 5:1. Using an organic solvent the molar ratio is in particular between 1:1 and 2:1.
  • the molar ratio of acid catalyst to starting compound of formula (2) preferably lies between 1:1 and 0.001:1, in particular between 0.01:1 and 0.05:1.
  • the resulting 2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivative can subsequently be hydrolyzed in the presence of a base and water to form the corresponding salt of formula 3
  • Y stands for an alkaline metal, an alkaline earth metal, or a substituted or unsubstituted ammonium group, preferably Na, Ca or a tetraalkyl-ammonium compound.
  • the hydrolysis is followed by conversion to the acetic acid according to formula 3 with Y ⁇ H.
  • the hydrolysis of the compound of formula (3) is preferably carried out with at least 1 base equivalent, in particular 1-1.5 base equivalents, relative to the compound of formula (3). In principle a larger excess can be used, but in practice this usually does not offer any advantages.
  • the reaction is preferably carried out at a temperature between ⁇ 20° C. and 60° C., in particular between 0° C. and 30° C.
  • the hydrolysis can for example be carried out in water, an organic solvent, for example an alcohol, in particular methanol or ethanol, an aromatic hydrocarbon, for example toluene, or a ketone, in particular acetone or methyl isobutyl ketone (MIBK), or a mixture of an organic solvent and water, optionally catalysed by a phase transfer catalyst (PTC) or addition of a cosolvent.
  • an organic solvent for example an alcohol, in particular methanol or ethanol
  • an aromatic hydrocarbon for example toluene
  • MIBK ketone
  • MIBK acetone or methyl isobutyl ketone
  • the hydrolysis can also be carried out enzymatically, the desired diastereomer optionally being hydrolyzed selectively.
  • enzymes that can suitably be used in the process according to the invention are enzymes with lipase or esterase activity, for example enzymes from Pseudomonas , in particular Pseudomonas fluorescens, Pseudomonas fragi; Burkholderia , for example Burkholderia cepacia; Chromobacterium , in particular Chromobacterium viscosum; Bacillus , in particular Bacillus thermocatenulatus, Bacillus licheniformis; Alcaligenes , in particular Alcaligenes faecalis; Aspergillus , in particular Aspergillus niger, Candida , in particular Candida antarctica, Candida rugosa, Candida lipolytica, Candida cylindracea; Geotrichum , in particular Geotrichum candidum; Humicola , in particular Humicola lanuginosa; Penicillium , in particular Penicillium cyclopium, Penicillium
  • an enzyme from Pseudomonas cepacia, Pseudomonas sp., Burkholderia cepacia , porcine pancreas, Rhizomucor miehei, Humicola lanuginosa, Candida rugosa or Candida antarctica or subtilisin. If an enantioselective enzyme is used, even further enantiomer enrichment is realized during the hydrolysis. Such enzymes can be obtained using commonly known technologies. Many enzymes are produced on a technical scale and are commercially available.
  • the salts (acids) obtained are novel.
  • the invention therefore also relates to these products of formula 3
  • X stands for a halogen, in particular Cl, Br or I, a tosylate or mesylate group, an acyloxy group with 3-10 carbon atoms, or a nitro-substituted benzene sulphonyl group
  • Y stands for H, an alkaline (earth) metal, or a substituted or unsubstituted ammonium group.
  • the compound of formula (3) can for example be esterified to form the corresponding tert. butyl ester using the following methods, which in general are described in literature:
  • the acid chloride can be prepared with the aid of for example SOCl 2 , POCl 3 , (COCl) 2 and catalyzed by for example dimethyl formamide (DMF) (J. Org. Chem. 35 2429 (1970));
  • the acyloxy group can subsequently be converted via solvolysis, in a way otherwise generally known, to a hydroxyl group.
  • the solvolysis can be performed using a base (Na 2 CO 3 , K 2 CO 3 , or sodium methanolate in methanol), optionally by simultaneous distillation of the methyl acetate formed.
  • the t-butyl ester of 2-(6-hydroxymethyl-1,3-dioxane-4-yl)acetic acid is a desirable intermediate product in the preparation of various statins, for example ZD-4522, as described in Drugs of the future, (1999), 24(5), 511-513 by M. Watanabe et al., Bioorg. & Med. Chem. (1997), 5(2), 437-444.
  • the invention therefore provides a novel, interesting route to these intermediate products and to the end products, in particular statins.
  • the starting compounds of formula 2 can for example be obtained as described in WO-A-96/31615.
  • the suspension can be used for the synthesis of compound V.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Catalysts (AREA)

Abstract

The invention relates to the preparation of 2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivatives of formula 1, where X stands for a leaving group, and R1, R2, and R3 each independently stand for an alkyl group with 1-3 carbon atoms from 4-hydroxy-6-X-substituted-methyl-tetrahydropyran-2-one compounds, where X is as defined above, with the aid of an acetalization agent, in the presence of an acid catalyst. The invention also relates to the novel compounds of formula 1 as well as salts and acids to be prepared from these, with the OR3 group in formula 1 being replaced by an OY group, where X, R1 and R2 have the meanings defined above and where Y stands for an alkaline (earth) metal or a substituted or unsubstituted ammonium group or stands for hydrogen, and to the novel compounds of formula 2. The products concerned are, after conversion into the t-butyl ester of 2-(6-hydroxymethyl-1,3-dioxane-4-yl)acetic acid, important as intermediary products in the preparation of statins.

Description

CROSS-REFERENCE TO RELATED APPLICATION
This application is a continuation of U.S. Ser. No. 10/333,351 filed Jan. 17, 2003, now U.S. Pat. No. 6,870,059 which is a National Stage of PCT/NL01/00535 filed Jul. 12, 2001 and which claims priority of the Netherlands application no. 1015744 filed Jul. 19, 2000. The contents of these applications are incorporated herein by reference.
The invention relates to a process for the preparation of a 2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivative of formula 1
Figure US07642363-20100105-C00001
where X stands for a leaving group, and R1, R2 and R3 each independently stand for an alkyl group with 1-3 carbon atoms, starting from a compound of formula 2
Figure US07642363-20100105-C00002
where X is as defined above, use being made of a suitable acetalization agent, in the presence of an acid catalyst.
The invention also relates to the new compounds of formula 1, as well as salts and acids of formula 3 that can be obtained therefrom
Figure US07642363-20100105-C00003
where R1 and R2 have the above-mentioned meanings and where Y stands for an alkaline (earth)metal or a substituted or non-substituted ammonium group or stands for hydrogen.
Applicant has surprisingly found that the 2-(6-substituted 1,3-dioxane-4-yl)-acetic acid derivative can be obtained selectively and in a high yield from the corresponding compound of formula (2), it being possible to prepare these products, which are relatively little stable, under mild conditions. This is all the more interesting since this provides a simple route via the corresponding salt, the corresponding t-butyl ester, and the 2-hydroxymethyl-substituted compound as intermediates in the preparation of HMG-CoA reductase inhibitors. Optionally the conversion proceeds (depending on the reaction conditions chosen) via an intermediary salt or ester, with the ring in the compound according to formula (2) being opened.
An added advantage of the process according to the invention is that both the starting compounds of formula (2) and the products of formula 3 are found to be crystalline compounds. This is advantageous in obtaining products with a (chemically and stereochemically) high purity. This is important in particular in view of the intended pharmaceutical application. For the intended application in particular the (4R,6S)-2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivative is important. It can be prepared from the corresponding 6-substituted-2,4,6-trideoxy-D-erythrohexose. The invention, therefore, also relates to the starting compounds of formula 1, in particular where X═Cl, and to particles of such compounds. In particular more than 90 wt. % of the particles has a length/diameter ratio between 1:1.5 and 1:6, preferably between 1:2 and 1:4.4 and a length of the particles between 0.05 and 2 mm, in particular between 0.1 and 1 mm. The invention also relates to such particles. The compound of formula II gives clear crystalline particles with a sharp melting point of 73-74° C. The products of formula 3 derived from the (4R,6S)-2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivative of formula 1 can according to the invention be prepared with an enantiomeric excess (e.e.) of more than 95%, in particular more than 99.5%, and with a diastereomeric excess (d.e.) of more than 90%, in particular more than 99.5%.
Examples of suitable leaving groups X that can be applied in the process according to the invention are halogens, in particular Cl, Br or I; tosylate groups; mesylate groups; acyloxy groups, in particular acetoxy and benzoyloxy groups; an aryloxy-, in particular benzyloxy-, or a nitro-substituted benzene sulphonyl group. For practical reasons Cl is preferably chosen as leaving group.
The groups R1, R2 and R3 each separately stand for an alkyl group with 1-3 carbon atoms, preferably methyl or ethyl. In practice R1=R2=R3=methyl is most preferred.
Examples of suitable acetalization agents that can be applied in the process according to the invention are dialkoxypropane compounds, with the alkoxy groups each preferably having 1-3 carbon atoms, for instance 2,2-dimethoxypropane or 2,2-diethoxypropane; alkoxypropene, with the alkoxy group preferably having 1-3 carbon atoms, for instance 2-methoxypropene or 2-ethoxypropene. Most preferred is 2,2-dimethoxypropane. This can optionally be formed in situ from acetone and methanol, preferably with water being removed.
As acid catalyst use can be made of the acid catalysts known for acetalization reactions, preferably non-nucleophilic strong acids, for example sulphonic acids, in particular p-toluene sulphonic acid, methane sulphonic acid of camphor sulphonic acid; inorganic acids with a non-nucleophilic anion, for example sulphuric acid, phosphoric acid: acid ion exchangers, for example DOWEX; or solid acids, for example the so-called heteropolyacids.
The acetalization can be carried out without using a separate solvent; if desired the reaction can also be carried out in an organic solvent. Examples of suitable organic solvents are ketones, in particular acetone, hydrocarbons, in particular aromatic hydrocarbons, for example toluene, chlorinated hydrocarbons, for example methylene chloride.
The temperature at which the acetalization reaction is carried out preferably lies between −20° C. and 60° C., in particular between 0° C. and 30° C. The acetalization reaction is preferably carried out under an inert atmosphere.
The molar ratio of acetalization agent to starting compound of formula (2) preferably lies between 1:1 and 20:1, in particular between 3:1 and 5:1. Using an organic solvent the molar ratio is in particular between 1:1 and 2:1.
The molar ratio of acid catalyst to starting compound of formula (2) preferably lies between 1:1 and 0.001:1, in particular between 0.01:1 and 0.05:1.
The resulting 2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivative can subsequently be hydrolyzed in the presence of a base and water to form the corresponding salt of formula 3
Figure US07642363-20100105-C00004
where Y stands for an alkaline metal, an alkaline earth metal, or a substituted or unsubstituted ammonium group, preferably Na, Ca or a tetraalkyl-ammonium compound. Optionally; the hydrolysis is followed by conversion to the acetic acid according to formula 3 with Y═H.
The hydrolysis of the compound of formula (3) is preferably carried out with at least 1 base equivalent, in particular 1-1.5 base equivalents, relative to the compound of formula (3). In principle a larger excess can be used, but in practice this usually does not offer any advantages.
The reaction is preferably carried out at a temperature between −20° C. and 60° C., in particular between 0° C. and 30° C.
The hydrolysis can for example be carried out in water, an organic solvent, for example an alcohol, in particular methanol or ethanol, an aromatic hydrocarbon, for example toluene, or a ketone, in particular acetone or methyl isobutyl ketone (MIBK), or a mixture of an organic solvent and water, optionally catalysed by a phase transfer catalyst (PTC) or addition of a cosolvent.
The hydrolysis can also be carried out enzymatically, the desired diastereomer optionally being hydrolyzed selectively.
Examples of enzymes that can suitably be used in the process according to the invention are enzymes with lipase or esterase activity, for example enzymes from Pseudomonas, in particular Pseudomonas fluorescens, Pseudomonas fragi; Burkholderia, for example Burkholderia cepacia; Chromobacterium, in particular Chromobacterium viscosum; Bacillus, in particular Bacillus thermocatenulatus, Bacillus licheniformis; Alcaligenes, in particular Alcaligenes faecalis; Aspergillus, in particular Aspergillus niger, Candida, in particular Candida antarctica, Candida rugosa, Candida lipolytica, Candida cylindracea; Geotrichum, in particular Geotrichum candidum; Humicola, in particular Humicola lanuginosa; Penicillium, in particular Penicillium cyclopium, Penicillium roquefortii, Penicillium camembertii; Rhizomucor, in particular Rhizomucor javanicus, Rhizomucor miehei; Mucor, in particular Mucor javanicus; Rhizopus, in particular Rhizopus oryzae, Rhizopus arhizus, Rhizopus delemar, Rhizopus niveus, Rhizopus japonicus, Rhizopus javanicus; porcine pancreas lipase, wheat germ lipase, bovine pancreas lipase, pig liver esterase. Preferably, use is made of an enzyme from Pseudomonas cepacia, Pseudomonas sp., Burkholderia cepacia, porcine pancreas, Rhizomucor miehei, Humicola lanuginosa, Candida rugosa or Candida antarctica or subtilisin. If an enantioselective enzyme is used, even further enantiomer enrichment is realized during the hydrolysis. Such enzymes can be obtained using commonly known technologies. Many enzymes are produced on a technical scale and are commercially available.
The salts (acids) obtained are novel. The invention therefore also relates to these products of formula 3
Figure US07642363-20100105-C00005
where X stands for a halogen, in particular Cl, Br or I, a tosylate or mesylate group, an acyloxy group with 3-10 carbon atoms, or a nitro-substituted benzene sulphonyl group and Y stands for H, an alkaline (earth) metal, or a substituted or unsubstituted ammonium group.
The resulting salt of formula 3 can subsequently be converted into the corresponding t-butyl ester (formula 1a with R3=t-butyl), in a way known per se.
Figure US07642363-20100105-C00006
In the process according to the invention the compound of formula (3) can for example be esterified to form the corresponding tert. butyl ester using the following methods, which in general are described in literature:
reaction with isobutene and strong acid, for example paratoluene sulphonic acid (pTS), sulphuric acid or a strongly acidic ion exchanger (U.S. Pat. No. 3,325,466);
reaction via the acid chloride and t-butanol, under the influence of a base, for example triethylamine (Et3N), dimethylamino pyridine (DMAP). The acid chloride can be prepared with the aid of for example SOCl2, POCl3, (COCl)2 and catalyzed by for example dimethyl formamide (DMF) (J. Org. Chem. 35 2429 (1970));
reaction via the acid chloride with Li-t-butanolate (Org. Synth. 51 96 (1971));
transesterification with t-butyl acetate under the influence of a strong acid (Z. Chem. 12(7) 264 (1972));
reaction of the salt with t-butyl bromide, preferably in DMF, dimethyl acetamide (DMAA), 1-methyl-2-pyrrolidinone(NMP) and using a phase transfer catalyst (PTC) (Tetr. Let. 34 (46) 7409 (1993));
reaction of the acid with t-butanol, 1,3-dicyclohexyl carbodiimide (DCC) and DMAP (Synth. Comm. 9, 542 (1979));
reaction of the acid with t-butyl-trichloro acetamidate (Tetr. Let. 39, 1557 (1998));
reaction of the salt with carboxyl diimidazole (CDI) and t-butanol;
reaction of the acid with pivaloyl chloride and t-butanol under the influence of DMAP or N-methyl-morpholin (NMM) (Bull. Chem. Soc. Japan 52 (7) 1989 (1979));
reaction of the salt with di-tert. butyl dicarbonate, DMAP and t-butanol (Synthesis 1063 (1994));
reaction of the acid with cyanuric chloride and pyridine or triethylamine (Org Process R&D 3, 172 (1999); Heterocycles 31 11, 2055 (1990)).
The resulting t-butyl ester of 2-(6-substituted-1,3-dioxane-4-yl)acetic acid can subsequently be converted into the 2-(6-hydroxymethyl-1,3-dioxane-4-yl)acetic acid, for example as described in U.S. Pat. No. 5,594,153 or in EP-A-1024139, in the presence of a tetraalkyl ammonium halogenide and/or a carboxylic acid in the salt, via conversion into a compound of formula 1a with R3=t-butyl and X=an acyloxy, for example an acetoxy group. The acyloxy group can subsequently be converted via solvolysis, in a way otherwise generally known, to a hydroxyl group. The solvolysis can be performed using a base (Na2CO3, K2CO3, or sodium methanolate in methanol), optionally by simultaneous distillation of the methyl acetate formed.
The t-butyl ester of 2-(6-hydroxymethyl-1,3-dioxane-4-yl)acetic acid is a desirable intermediate product in the preparation of various statins, for example ZD-4522, as described in Drugs of the future, (1999), 24(5), 511-513 by M. Watanabe et al., Bioorg. & Med. Chem. (1997), 5(2), 437-444. The invention therefore provides a novel, interesting route to these intermediate products and to the end products, in particular statins.
The starting compounds of formula 2 can for example be obtained as described in WO-A-96/31615.
The invention will be elucidated with reference to the following examples, without however being restricted by these.
EXAMPLE I Preparation of (4R,6S)-4-hydroxy-6-chloromethyl-tetrahydropyran-2-one (Compound II; Covered by Formula 2)
At room temperature 2.1 ml bromine was added in 45 minutes to a mixture of 6.7 g (40 mmol) 6-chloro-2,4,6-trideoxy-D-erythro-hexose (compound I; prepared according to the method described in WO-A-96/31615) and 6.7 g sodium bicarbonate in 40 ml methylene chloride and 10 ml water. CO2 gas escaped, while the pH remained at 5. After stirring for one hour, according to gas-liquid chromatography (GLC) the starting material had been fully converted. The bromine excess was neutralized with solid Na2S2O3. After phase separation the water phase was extracted with 2 times 100 ml ethyl acetate. The combined organic phases were dried over Na2SO4 and filtered. After rotavap evaporation 5.5 g yellow oil was obtained (82% yield of the compound of formula (2) with X═Cl relative to compound I).
1H NMR (200 MHz, CDCl3): δ 1.8-2.1 (m, 2H); 2.6-2.7 (m, 2H); 3.5-3.8 (m, 2H(CH2Cl)); 4.4 (m, 1H); 4.9 (m, 1H).
EXAMPLE II Preparation of (4R,6S)-4-hydroxy-6-chloromethyl-tetrahydropyran-2-one (Compound II; Covered by Formula 2)
To a solution of 75 g (450 mmole) compound I in 390 ml water was added 114 g (715 mmole) of bromine at 15-25° C. in 3 hours. The pH of the reaction mixture was maintained at 5-6 via the simultaneous addition of sodium carbonate (88 g total amount). The excess of bromine was neutralized with sodium bisulfite. The product was extracted from the water phase with ethyl acetate (counter-current extraction).
The product was crystallized from ethyl acetate/heptane (125 g/62 g). After cooling to 0° C., the crystals were filtered, washed with 50 ml of heptane/ethyl acetate (w:w=9:1) and dried, yielding 49.2 g (67% relative to compound I) of compound II as colourless needles (m.p. 73-74° C.).
EXAMPLE III Preparation of (4R-cis)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxane-4-yl acetic acid methyl ester (Compound III)
5.5 g of compound II as obtained in example I was added to 20 ml commercial dimethoxy propane and 100 mg p-toluene sulphonic acid monohydrate at room temperature. After stirring for one hour at room temperature GLC analysis showed that full conversion had taken place and a clear solution had been formed. After addition of 500 mg NaHCO3 stirring took place for 30 minutes at room temperature. After filtration and rotavap evaporation 7.1 g compound III was obtained as a light-yellow oil (91% relative to compound II).
1H NMR (200 MHz, CDCl3): δ 1.25 (dt, 1H); 1.40 (s, 3H); 1.47 (s, 3H); 1.79 (dt, 1H); 2.42 (dd, 1H); 2.58 (dd, 1H); 3.40 (dd, 1H); 3.52 (dd, 1H); 3.70 (s, 3H); 4.1 (m, 1H); 4.35 (m, 1H).
EXAMPLE IV Preparation of (4R-cis)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxane-4-yl acetic acid methyl ester (Compound III)
To a solution of 49.2 g (300 mmole) of compound II in 100 ml of toluene was added 47 g (450 mmole) dimethoxy propane and 850 mg p-toluene sulphonic acid monohydrate (4.5 mmole).
After stirring for one hour at room temperature, GLC analysis showed complete conversion of compound II.
The toluene phase was washed with 50 ml of a 0.2N NaOH solution in water. After evaporation 67 g of compound III was obtained as a light-yellow oil (94% relative to compound II).
EXAMPLE V (4R-cis)-(6-chloromethyl)-2,2-dimethyl-1,3-dioxane-4-yl-acetic acid, sodium salt (Compound IV)
55 g (233 mmol) of compound III was added to 200 ml water. At room temperature 20 g of a 50% NaOH solution in water was added dropwise in 2 hours at pH=12. The hydrolysis was monitored using GLC. After 20 g the pH remained constant. Concentrated hydrochloric acid was used to lower the pH to 10. The water phase was washed with 100 ml ethyl acetate and evaporated using a rotavap. The oil formed was dried by stripping with absolute ethanol and toluene. The solid was stirred into 200 ml acetone, filtered and washed with cold acetone. Yield after vacuum drying: 45.6 g=80% Na salt relative to compound III.
1H NMR (200 MHz, CDCl3/CD3OD): δ 1.21 (dt, 1H); 1.36 (s, 3H); 1.49 (s, 3H); 1.79 (dt, 1H); 2.25 (dd, 1H); 2.45 (dd, 1H); 3.46 (m, 2H); 4.11 (m, 1H); 4.36 (m, 1H).
EXAMPLE VI (4R-cis)-(6-chloromethyl)-2,2-dimethyl-1,3-dioxane-4-yl-acetic acid, sodium salt (Compound IV)
Starting from 49.2 g compound I, a solution of compound III in toluene was prepared as described in example IV.
5 g methanol and 25 ml of water were added. At room temperature 25 g of a 50% solution of NaOH in water was added dropwise in 1 hour.
After stirring for 4 hours at room temperature, GLC analysis indicated complete hydrolysis.
The excess of base was neutralized to pH 8.5-9.5 with 33% HCl solution in water. The waterphase was separated and dried via azeotropic distillation using 470 ml of toluene, yielding 65 g compound IV as a 16 w/w % suspension in toluene with KF<0.1%.
The suspension can be used for the synthesis of compound V.
EXAMPLE VII (4R-cis)-(6-chloromethyl)-2,2 dimethyl-1,3-dioxane-4-yl-acetic acid, t-butyl ester (Compound V)
45.5 g IV, sodium salt (186 mmol) was added to a solution of 159 g ditert. butyl dicarbonate in 1400 ml dry tert. butanol. After addition of 6.8 g dimethylamino pyridine stirring took place for 16 hours at 40° C. The reaction mixture was poured out into 1500 ml ethyl acetate and 1000 ml saturated ammonium chloride. The water phase was re-extracted with 1500 ml ethyl acetate. The combined organic phases were washed with 600 ml saturated NaCl solution. The organic layer was dried over Na2SO4, filtered and then evaporated under vacuum, yielding 51.9 g yellow oil (100% relative to compound IV).
1H NMR (200 MHz, CDCl3): δ 1.15-1.33 (m, 1H); 1.40 (s, 3H); 1.45 (s, 3H); 1.47 (s, 9H) 1.77 (dt, 1H); 2.33 (dd, 1H); 2.46 (dd, 1H); 3.40 (dd, 1H); 3.49 (dd, 1H) 4.08 (m, 1H); 4.28 (m, 1H).
EXAMPLE VIII (4R-cis)-6-[(acetoxy)methyl]-2,2-dimethyl-1,3-dioxane-4-yl-acetic acid, t-butyl ester (Compound VI)
Starting from 33 g of compound V obtained according to example VII, in 16 hours 29 g of compound VI was obtained at 100° C. according to U.S. Pat. No. 5,457,227 (using 40 g tetra-n-butyl ammonium acetate and in 200 ml DMF), as a solid after crystallization from 75 ml heptane.
1H NMR (200 MHz, CDCl3): δ 1.1-1.3 (dt, 1H); 1.39 (s, 3H); 1.45 (s, 9H); 1.47 (s, 3H); 1.57 (dt, 1H); 2.08 (s, 3H); 2.32 (dd, 1H); 2.46 (dd, 1H); 4.0-4.2 (m, 3H); 4.3 (m, 1H).
EXAMPLE IX (4R-cis)-6-[hydroxymethyl]-2,2-dimethyl-1,3-dioxane-4-yl-acetic acid, t-butyl ester (Compound VII)
Starting from 29 g of compound VI according to example V, 25.0 g compound VII was obtained as a light-yellow oil with e.e.=100%, d.e.=99.9% (according to GLC) according to U.S. Pat. No. 5,457,227 (use being made of 6.9 g potassium carbonate in 300 ml methanol).
1H NMR (200 MHz, CDCl3): Spectrum was in line with literature (Synthesis 1014, 1995).

Claims (12)

The invention claimed is:
1. A compound of formula (3),
Figure US07642363-20100105-C00007
wherein
each R1 and R2 is independently an alkyl group with 1-3 carbon atoms;
Y is an alkaline metal, an alkaline earth metal, or a tetraalkyl-substituted or unsubstituted ammonium group; and
X is a tosylate group, a mesylate group, an acyloxy group, an aryloxy-substituted benzene sulfonyl group or a nitro-substituted benzene sulfonyl group, wherein the acyloxy group has 3-10 carbon atoms.
2. The compound of claim 1, wherein Y is Na, Ca or tetraalkyl ammonium.
3. The compound of claim 1, wherein said compound is in the 4R,6S form.
4. The compound of claim 3, wherein said compound has an enantiomeric excess of more than 90%.
5. The compound of claim 4, wherein said compound has an enantiomeric excess of more than 99%.
6. The compound of claim 1, wherein each R1 and R2 is independently methyl.
7. A compound of formula (1),
Figure US07642363-20100105-C00008
wherein
each R1, R2 and R3 is independently an alkyl group with 1-3 carbon atoms; and
X is acyloxy, a tosylate group, an aryloxy-substituted benzene sulfonyl group or a nitro-substituted benzene sulfonyl group.
8. A compound having formula (2) in the (4R,6S) form,
Figure US07642363-20100105-C00009
where X is a tosylate group, a mesylate group, an acyloxy group, an aryloxy-substituted benzene sulfonyl group, or a nitro-substituted benzene sulfonyl group.
9. The compound of claim 8, wherein the compound exists as particles having a particle length/diameter ratio between 1:1.5 and 1:6.
10. The compound of claim 8, wherein the compound exists as particles having a particle length between 0.05 and 2 mm.
11. The compound of claim 8, wherein the compound exists as particles having a particle length between 0.1 and 1 mm.
12. The compound of claim 8, wherein said acyloxy group has 3-10 carbons.
US11/053,090 2000-07-19 2005-02-07 Process for the preparation of 2-(6-substituted-1,3-dioxane-4-YL) acetic acid derivatives Expired - Lifetime US7642363B2 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US11/053,090 US7642363B2 (en) 2000-07-19 2005-02-07 Process for the preparation of 2-(6-substituted-1,3-dioxane-4-YL) acetic acid derivatives
US12/625,156 US7989643B2 (en) 2000-07-19 2009-11-24 Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivatives
US13/166,607 US20110251406A1 (en) 2000-07-19 2011-06-22 Process for the preparation of 2-(6-substituted-1,-3-dioxane-4-yl) acetic acid derivatives

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
NL1015744 2000-07-19
NL1015744A NL1015744C2 (en) 2000-07-19 2000-07-19 Process for the preparation of 2- (6-substituted-1,3-dioxan-4-yl) acetic acid derivatives.
US10/333,351 US6870059B2 (en) 2000-07-19 2001-07-12 Process for the preparation of 2-(6-substituted-1,-3-dioxane-4-yl)acetic acid derivatives
PCT/NL2001/000535 WO2002006266A1 (en) 2000-07-19 2001-07-12 Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivatives
US11/053,090 US7642363B2 (en) 2000-07-19 2005-02-07 Process for the preparation of 2-(6-substituted-1,3-dioxane-4-YL) acetic acid derivatives

Related Parent Applications (3)

Application Number Title Priority Date Filing Date
US10333351 Continuation 2001-07-12
PCT/NL2001/000535 Continuation WO2002006266A1 (en) 2000-07-19 2001-07-12 Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivatives
US10/333,351 Continuation US6870059B2 (en) 2000-07-19 2001-07-12 Process for the preparation of 2-(6-substituted-1,-3-dioxane-4-yl)acetic acid derivatives

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/625,156 Continuation US7989643B2 (en) 2000-07-19 2009-11-24 Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivatives

Publications (2)

Publication Number Publication Date
US20050148785A1 US20050148785A1 (en) 2005-07-07
US7642363B2 true US7642363B2 (en) 2010-01-05

Family

ID=19771761

Family Applications (4)

Application Number Title Priority Date Filing Date
US10/333,351 Expired - Lifetime US6870059B2 (en) 2000-07-19 2001-07-12 Process for the preparation of 2-(6-substituted-1,-3-dioxane-4-yl)acetic acid derivatives
US11/053,090 Expired - Lifetime US7642363B2 (en) 2000-07-19 2005-02-07 Process for the preparation of 2-(6-substituted-1,3-dioxane-4-YL) acetic acid derivatives
US12/625,156 Expired - Fee Related US7989643B2 (en) 2000-07-19 2009-11-24 Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivatives
US13/166,607 Abandoned US20110251406A1 (en) 2000-07-19 2011-06-22 Process for the preparation of 2-(6-substituted-1,-3-dioxane-4-yl) acetic acid derivatives

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US10/333,351 Expired - Lifetime US6870059B2 (en) 2000-07-19 2001-07-12 Process for the preparation of 2-(6-substituted-1,-3-dioxane-4-yl)acetic acid derivatives

Family Applications After (2)

Application Number Title Priority Date Filing Date
US12/625,156 Expired - Fee Related US7989643B2 (en) 2000-07-19 2009-11-24 Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivatives
US13/166,607 Abandoned US20110251406A1 (en) 2000-07-19 2011-06-22 Process for the preparation of 2-(6-substituted-1,-3-dioxane-4-yl) acetic acid derivatives

Country Status (29)

Country Link
US (4) US6870059B2 (en)
EP (2) EP1700854B1 (en)
JP (2) JP5006499B2 (en)
KR (3) KR20080078925A (en)
CN (3) CN1443183A (en)
AT (1) ATE340790T1 (en)
AU (2) AU7583001A (en)
BR (1) BR0112535A (en)
CA (1) CA2415963C (en)
CY (1) CY1105881T1 (en)
CZ (1) CZ302718B6 (en)
DE (1) DE60123444T2 (en)
DK (1) DK1317440T3 (en)
EE (1) EE200300024A (en)
ES (2) ES2387313T3 (en)
HU (1) HUP0303166A3 (en)
IL (3) IL153980A0 (en)
IS (2) IS2386B (en)
MX (1) MXPA03000498A (en)
NL (1) NL1015744C2 (en)
NO (1) NO328935B1 (en)
NZ (1) NZ523703A (en)
PL (1) PL207115B1 (en)
PT (1) PT1317440E (en)
RU (1) RU2266903C2 (en)
SK (2) SK287756B6 (en)
UA (1) UA77944C2 (en)
WO (1) WO2002006266A1 (en)
ZA (1) ZA200300478B (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070255060A1 (en) * 2003-10-24 2007-11-01 Tetsuo Okada Process for the Manufacture of the Calcium Salt of Rosuvastatin (E)-7-'4-(4-Fluorophenyl)-6-Isopropyl-2-'Methyl (Methylsulfonyl) Amino ! Pyrmidin -5-Yl! (3R, 5S)-3,5-Dihydroxyhept-6-Enoic Acid and Crystalline Intermediates Thereof
US20080058520A1 (en) * 2001-07-13 2008-03-06 Akio Matsushita Preparation of Aminopyrimidine Compounds
US20080188657A1 (en) * 2006-12-01 2008-08-07 Astrazeneca Uk Limited Chemical process
US20080207903A1 (en) * 2004-12-24 2008-08-28 Michael Butters Chemical Process
US20080221323A1 (en) * 2003-06-05 2008-09-11 Jeffrey Norman Crabb Production of Rosuvastatin Calcium Salt
US20090286819A1 (en) * 2002-08-13 2009-11-19 Astrazeneca Ab Process for Preparing the Calcium Salt of Rosuvastatin
US20100136339A1 (en) * 2000-07-19 2010-06-03 Astrazeneca Uk Ltd. Process for the Preparation of 2-(6-Substituted-1,3-Dioxane-4-yl)Acetic Acid Derivatives
US20100209984A1 (en) * 2000-05-09 2010-08-19 Astrazeneca Uk Limited Process for the preparation of dihydroxy esters and derivatives thereof
US20100228028A1 (en) * 2005-07-08 2010-09-09 Michael Butters Processes for the manufacture of rosuvastatin and intermediates
US8436167B2 (en) 2003-09-10 2013-05-07 Astrazeneca Uk Limited Chemical compounds

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1323717A1 (en) * 2001-12-27 2003-07-02 Dsm N.V. Process for the preparation of 2-(6-Substituted-1,3-Dioxane-4-yL) acetic acid derivatives
EP1375493A1 (en) * 2002-06-17 2004-01-02 Dsm N.V. Process for the preparation of an dioxane acetic acid ester
AU2003263031A1 (en) 2002-09-20 2004-04-08 Diversa Corporation Chemoenzymatic methods for the synthesis of statins and stain intermediates
US9740817B1 (en) 2002-10-18 2017-08-22 Dennis Sunga Fernandez Apparatus for biological sensing and alerting of pharmaco-genomic mutation
DK1578731T3 (en) 2002-12-16 2010-02-15 Astrazeneca Uk Ltd Process for Preparation of Pyrimidine Compounds
CN1780826B (en) 2003-05-02 2010-05-26 帝斯曼知识产权资产管理有限公司 Process for preparing (4-hydroxy-6-oxo-tetrahydropyran-2-yl)acetonitrile and derivatives thereof
US8346482B2 (en) 2003-08-22 2013-01-01 Fernandez Dennis S Integrated biosensor and simulation system for diagnosis and therapy
GB0321827D0 (en) * 2003-09-18 2003-10-15 Astrazeneca Uk Ltd Chemical compounds
DE10352659B4 (en) * 2003-11-11 2007-09-13 Ratiopharm Gmbh Process for the preparation of statins and tetrahydropyranone derivatives for use in the process
US7264743B2 (en) * 2006-01-23 2007-09-04 Lam Research Corporation Fin structure formation
WO2010118757A1 (en) * 2009-04-15 2010-10-21 Pharmathen S.A. Improved process for the preparation of fluvastatin and salts thereof
GB2482525A (en) * 2010-08-05 2012-02-08 Phoenix Chemicals Ltd A process for the production of acyloxymethyldioxanylacetic derivatives
WO2012032035A1 (en) 2010-09-09 2012-03-15 Dsm Sinochem Pharmaceuticals Netherlands B.V. Salts of 7-amino-3,5-dihydroxyheptanoic acid esters
MX2013002809A (en) 2010-09-16 2013-04-29 Dsm Sinochem Pharm Nl Bv Esters of hexanoic acids as intermediates for the preparation of atorvastatin.
ES2601479T3 (en) 2011-01-18 2017-02-15 Dsm Sinochem Pharmaceuticals Netherlands B.V. Process for the preparation of diolsulfones
CN103313983B (en) 2011-01-18 2016-06-29 中化帝斯曼制药有限公司荷兰公司 Process for preparing statin compounds in the presence of bases
SI2665721T1 (en) 2011-01-18 2015-10-30 Dsm Sinochem Pharmaceuticals Netherlands B.V. Methyltetrazole sulfides and sulfones
WO2013083719A1 (en) * 2011-12-09 2013-06-13 Dsm Sinochem Pharmaceuticals Netherlands B.V. Process for the preparation of a thioprecursor for statins
EP2788342B1 (en) 2011-12-09 2018-01-24 DSM Sinochem Pharmaceuticals Netherlands B.V. Process for the preparation of a statin precursor
JP6065862B2 (en) * 2013-04-10 2017-01-25 信越化学工業株式会社 Pattern forming method, resist composition, polymer compound and monomer
WO2014203045A1 (en) 2013-06-20 2014-12-24 Lupin Limited A novel, green and cost effective process for synthesis of tert-butyl (3r,5s)-6-oxo-3,5-dihydroxy-3,5-o-isopropylidene-hexanoate
CN105624127B (en) * 2014-10-28 2019-07-26 上海弈柯莱生物医药科技有限公司 A kind of glucose dehydrogenase and its application in the synthesis of statins intermediates

Citations (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB885516A (en) 1958-01-16 1961-12-28 Arthur Henry Clarkson Higher fatty acid esters of dextran
US3325466A (en) 1961-01-11 1967-06-13 American Cyanamid Co Tertiary butyl group as a carboxyl protecting group in the synthesis of peptides
US3992432A (en) 1967-04-05 1976-11-16 Continental Oil Company Phase transfer catalysis of heterogeneous reactions by quaternary salts
WO1991013876A1 (en) 1990-03-16 1991-09-19 Rhone-Poulenc Rorer Limited Imidazoles
JPH04266879A (en) 1991-02-21 1992-09-22 Chisso Corp Production of optically active compound for synthesizing physiologically active substance and optically active intermediate compound
WO1993006235A1 (en) 1991-09-20 1993-04-01 Zeneca Limited Process for the preparation of enantiomerically pure 4-hydroxytetrahydro-2-pyranone derivatives
WO1993008823A1 (en) 1991-11-06 1993-05-13 Tanabe Seiyaku Co., Ltd. Guanidinyl and related cell adhesion modulation compounds
US5278313A (en) 1992-03-27 1994-01-11 E. R. Squibb & Sons, Inc. Process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-COA reductase inhibitors
US5292891A (en) * 1991-02-21 1994-03-08 Chisso Corporation Optically active 2,2-dimethyl-1,3-dioxin-4-ones and method for preparing same and method for preparing optically active compound for synthesis of physiologically active substance and optically active intermediate compound
US5294724A (en) * 1989-09-08 1994-03-15 Hoechst Aktiengesellschaft 4-hydroxytetrahydropyran-2-ones and the corresponding dihydroxycarboxylic acid derivatives, salts and esters and a process for their preparation
US5449793A (en) * 1993-06-04 1995-09-12 Chisso Corporation Process for producing an optically active 1,5-disubstituted-2,4-O-isopropylidene-2,4-dihydroxypentane
WO1996031615A1 (en) 1995-04-05 1996-10-10 The Scripps Research Institute Use of 2-deoxyribose-5-phosphate aldolase to prepare 2-deoxyfucose, analogues and derivatives
WO1997019185A1 (en) 1995-11-23 1997-05-29 Zeneca Limited Production of optically active 2-substituted tetrahydropyran-4-ones
WO1997019917A1 (en) 1995-11-28 1997-06-05 L'oreal METHOD FOR PREPARING (+)COMPACTIN AND (+)MEVINOLIN ANALOG COMPOUNDS HAVING A β-HYDROXY-δ-LACTONE GROUPING
WO1999057109A1 (en) 1998-04-30 1999-11-11 Kaneka Corporation Process for producing 6-cyanomethyl-1,3-dioxane-4-acetic acid derivatives
WO2000008011A1 (en) 1998-08-05 2000-02-17 Kaneka Corporation Process for the preparation of optically active 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivatives
WO2000034264A1 (en) 1998-12-10 2000-06-15 Kaneka Corporation Process for producing simvastatin
WO2000049014A1 (en) 1999-02-17 2000-08-24 Astrazeneca Ab Process for the production of tert-butyl (e)-(6-[2- [4-(4-fluorophenyl) -6-isopropyl-2-[ methyl (methylsulfonyl) amino] pyrimidin-5-yl] vinyl](4r, 6s)-2,2-dimethyl [1,3]dioxan-4-yl) acetate
WO2000068221A1 (en) 1999-05-06 2000-11-16 EGIS Gyógyszergyár Rt. Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof
US6278001B1 (en) 1995-11-28 2001-08-21 L'oréal Method for preparing (+) compactin and (+) mevinolin analog compounds having a β-hydroxy-δ-lactone grouping
WO2001072706A1 (en) 2000-03-28 2001-10-04 Biocon India Limited Synthesis of [r-(r*,r*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin)
WO2001085975A1 (en) 2000-05-09 2001-11-15 Avecia Limited Process for the preparation of dihydroxy esters and derivatives thereof
US6340767B1 (en) 1999-06-04 2002-01-22 Kaneka Corporation Processes for the preparation of 5-hydroxy-3-oxopentanoic acid derivatives
WO2002006266A1 (en) 2000-07-19 2002-01-24 Dsm N.V. Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivatives
WO2003006439A1 (en) 2001-07-13 2003-01-23 Astrazeneca Uk Limited Preparation of aminopyrimidine compounds
WO2003059901A1 (en) 2001-12-27 2003-07-24 Astrazeneca Uk Ltd Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl) acetic acid derivates
WO2003087112A1 (en) 2002-04-09 2003-10-23 Cls Laboratories, Inc. Chiral intermediate and process for the production thereof
WO2003106447A1 (en) 2002-06-17 2003-12-24 Dsm Ip Assests B.V. Process for the preparation of dioxane acetic acid esters
WO2004014872A1 (en) 2002-08-13 2004-02-19 Astrazeneca Uk Limited Process for preparing the calcium salt of rosuvastatin
WO2004054986A2 (en) 2002-12-16 2004-07-01 Astrazeneca Uk Limited Process for the preparation of pyrimidine compounds
WO2004103977A2 (en) 2003-05-21 2004-12-02 Ciba Specialty Chemicals Holding Inc. Process for the preparation of pyrimidine derivatives
WO2004108691A1 (en) 2003-06-05 2004-12-16 Astrazeneca Uk Limited Improved production of rosuvastatin calcium salt
WO2004113314A1 (en) 2003-06-23 2004-12-29 Biocon Limited Novel boronate esters
WO2005023779A1 (en) 2003-09-10 2005-03-17 Astrazeneca Uk Limited Crystalline form of bis [(e)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3r,5s)-3,5-dihydroxyhept-6 -enoicacid] calcium salt
WO2005028450A1 (en) 2003-09-18 2005-03-31 Astrazeneca Uk Limited Polymorphic forms of a known antihyperlipemic agent
WO2005042522A1 (en) 2003-10-24 2005-05-12 Astrazeneca Uk Limited Process for the manufacture of the calcium salt of rosuvatatin (e)-7-`4- (4-fluorophenyl) -6-isopropyl-2-`methyl (methylsulfonyl) amino ! pyrimidin -5-yl ! (3r, 5s) -3, 5-dihydroxyhept-6-enoic acid and crystalline intermediates thereof
WO2005063728A2 (en) 2003-12-24 2005-07-14 Teva Pharmaceutical Industries Ltd. Process for preparation of statins with high syn to anti ratio
US20060004200A1 (en) 2004-06-21 2006-01-05 Srinivasulu Gudipati Processes to produce intermediates for rosuvastatin
US20060040898A1 (en) 2002-02-25 2006-02-23 Puthiaparampil Tom T Novel boronate esters
WO2006067456A2 (en) 2004-12-24 2006-06-29 Astrazeneca Uk Limited Process for preparing rosuvastatin

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US544390A (en) * 1895-08-13 Chimney-cowl
CA2048716A1 (en) * 1990-08-17 1992-02-18 William B. Mattingly, Iii Absorbent articles with integral release system and methods of making same
FR2696460B1 (en) * 1992-10-05 1994-11-25 Rhone Poulenc Rorer Sa Process for the preparation of taxane derivatives.
CA2380997A1 (en) * 2000-06-05 2001-12-13 Kaneka Corporation Process for preparing optically active 2-¬6-(hydroxy-methyl)-1,3-dioxan-4-yl|acetic acid derivatives
JP4266879B2 (en) 2004-05-12 2009-05-20 大阪瓦斯株式会社 Gasification furnace and combined recycling equipment
GB0514078D0 (en) 2005-07-08 2005-08-17 Astrazeneca Uk Ltd Chemical process
TW200831469A (en) * 2006-12-01 2008-08-01 Astrazeneca Uk Ltd Chemical process

Patent Citations (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB885516A (en) 1958-01-16 1961-12-28 Arthur Henry Clarkson Higher fatty acid esters of dextran
US3325466A (en) 1961-01-11 1967-06-13 American Cyanamid Co Tertiary butyl group as a carboxyl protecting group in the synthesis of peptides
US3992432A (en) 1967-04-05 1976-11-16 Continental Oil Company Phase transfer catalysis of heterogeneous reactions by quaternary salts
US5294724A (en) * 1989-09-08 1994-03-15 Hoechst Aktiengesellschaft 4-hydroxytetrahydropyran-2-ones and the corresponding dihydroxycarboxylic acid derivatives, salts and esters and a process for their preparation
WO1991013876A1 (en) 1990-03-16 1991-09-19 Rhone-Poulenc Rorer Limited Imidazoles
JPH04266879A (en) 1991-02-21 1992-09-22 Chisso Corp Production of optically active compound for synthesizing physiologically active substance and optically active intermediate compound
US5292891A (en) * 1991-02-21 1994-03-08 Chisso Corporation Optically active 2,2-dimethyl-1,3-dioxin-4-ones and method for preparing same and method for preparing optically active compound for synthesis of physiologically active substance and optically active intermediate compound
US5443970A (en) 1991-09-20 1995-08-22 Zeneca Limited Pyranones
WO1993006235A1 (en) 1991-09-20 1993-04-01 Zeneca Limited Process for the preparation of enantiomerically pure 4-hydroxytetrahydro-2-pyranone derivatives
WO1993008823A1 (en) 1991-11-06 1993-05-13 Tanabe Seiyaku Co., Ltd. Guanidinyl and related cell adhesion modulation compounds
US5594153A (en) 1992-03-27 1997-01-14 E. R. Squibb & Sons, Inc. Process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-COA reductase inhibitors
US5457227A (en) 1992-03-27 1995-10-10 E. R. Squibb & Sons, Inc. Process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-CoA reductase inhibitors
US5278313A (en) 1992-03-27 1994-01-11 E. R. Squibb & Sons, Inc. Process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-COA reductase inhibitors
US5449793A (en) * 1993-06-04 1995-09-12 Chisso Corporation Process for producing an optically active 1,5-disubstituted-2,4-O-isopropylidene-2,4-dihydroxypentane
WO1996031615A1 (en) 1995-04-05 1996-10-10 The Scripps Research Institute Use of 2-deoxyribose-5-phosphate aldolase to prepare 2-deoxyfucose, analogues and derivatives
WO1997019185A1 (en) 1995-11-23 1997-05-29 Zeneca Limited Production of optically active 2-substituted tetrahydropyran-4-ones
EP0862646A1 (en) 1995-11-23 1998-09-09 Zeneca Limited Production of optically active 2-substituted tetrahydropyran-4-ones
WO1997019917A1 (en) 1995-11-28 1997-06-05 L'oreal METHOD FOR PREPARING (+)COMPACTIN AND (+)MEVINOLIN ANALOG COMPOUNDS HAVING A β-HYDROXY-δ-LACTONE GROUPING
US6278001B1 (en) 1995-11-28 2001-08-21 L'oréal Method for preparing (+) compactin and (+) mevinolin analog compounds having a β-hydroxy-δ-lactone grouping
WO1999057109A1 (en) 1998-04-30 1999-11-11 Kaneka Corporation Process for producing 6-cyanomethyl-1,3-dioxane-4-acetic acid derivatives
US6344569B1 (en) * 1998-04-30 2002-02-05 Kaneka Corporation Process for producing 6-cyanomethyl-1,3-dioxane-4-acetic acid derivatives
WO2000008011A1 (en) 1998-08-05 2000-02-17 Kaneka Corporation Process for the preparation of optically active 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivatives
EP1024139A1 (en) 1998-08-05 2000-08-02 Kaneka Corporation Process for the preparation of optically active 2- 6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivatives
WO2000034264A1 (en) 1998-12-10 2000-06-15 Kaneka Corporation Process for producing simvastatin
US6331641B1 (en) 1998-12-10 2001-12-18 Kaneka Corporation Process for producing simvastatin
WO2000049014A1 (en) 1999-02-17 2000-08-24 Astrazeneca Ab Process for the production of tert-butyl (e)-(6-[2- [4-(4-fluorophenyl) -6-isopropyl-2-[ methyl (methylsulfonyl) amino] pyrimidin-5-yl] vinyl](4r, 6s)-2,2-dimethyl [1,3]dioxan-4-yl) acetate
US6844437B1 (en) 1999-02-17 2005-01-18 Astrazeneca Ab Process for the production of tert-butyl (E)-(6-[2-[4-(4-flurophenyl)-6-isopropyl-2-[methyl(methylsufonyl)amino]pyrimidin-5-yl]vinyl]4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate
US6784171B2 (en) 1999-02-17 2004-08-31 Astrazeneca Process for the production of tert-butyl (E)-(6-[2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]vinyl](4R,6S)-2, 2-dimethyl[1, 3]dioxan-4-yl)acetate
WO2000068221A1 (en) 1999-05-06 2000-11-16 EGIS Gyógyszergyár Rt. Salts of 2,2-dimethyl-1,3-dioxane intermediates and process for the preparation thereof
US6340767B1 (en) 1999-06-04 2002-01-22 Kaneka Corporation Processes for the preparation of 5-hydroxy-3-oxopentanoic acid derivatives
WO2001072706A1 (en) 2000-03-28 2001-10-04 Biocon India Limited Synthesis of [r-(r*,r*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin)
WO2001085975A1 (en) 2000-05-09 2001-11-15 Avecia Limited Process for the preparation of dihydroxy esters and derivatives thereof
WO2002006266A1 (en) 2000-07-19 2002-01-24 Dsm N.V. Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivatives
US6870059B2 (en) 2000-07-19 2005-03-22 Astrazeneca Uk Ltd. Process for the preparation of 2-(6-substituted-1,-3-dioxane-4-yl)acetic acid derivatives
WO2003006439A1 (en) 2001-07-13 2003-01-23 Astrazeneca Uk Limited Preparation of aminopyrimidine compounds
WO2003059901A1 (en) 2001-12-27 2003-07-24 Astrazeneca Uk Ltd Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl) acetic acid derivates
US20060040898A1 (en) 2002-02-25 2006-02-23 Puthiaparampil Tom T Novel boronate esters
WO2003087112A1 (en) 2002-04-09 2003-10-23 Cls Laboratories, Inc. Chiral intermediate and process for the production thereof
WO2003106447A1 (en) 2002-06-17 2003-12-24 Dsm Ip Assests B.V. Process for the preparation of dioxane acetic acid esters
WO2004014872A1 (en) 2002-08-13 2004-02-19 Astrazeneca Uk Limited Process for preparing the calcium salt of rosuvastatin
WO2004054986A2 (en) 2002-12-16 2004-07-01 Astrazeneca Uk Limited Process for the preparation of pyrimidine compounds
WO2004103977A2 (en) 2003-05-21 2004-12-02 Ciba Specialty Chemicals Holding Inc. Process for the preparation of pyrimidine derivatives
WO2004108691A1 (en) 2003-06-05 2004-12-16 Astrazeneca Uk Limited Improved production of rosuvastatin calcium salt
WO2004113314A1 (en) 2003-06-23 2004-12-29 Biocon Limited Novel boronate esters
WO2005023779A1 (en) 2003-09-10 2005-03-17 Astrazeneca Uk Limited Crystalline form of bis [(e)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3r,5s)-3,5-dihydroxyhept-6 -enoicacid] calcium salt
WO2005028450A1 (en) 2003-09-18 2005-03-31 Astrazeneca Uk Limited Polymorphic forms of a known antihyperlipemic agent
WO2005042522A1 (en) 2003-10-24 2005-05-12 Astrazeneca Uk Limited Process for the manufacture of the calcium salt of rosuvatatin (e)-7-`4- (4-fluorophenyl) -6-isopropyl-2-`methyl (methylsulfonyl) amino ! pyrimidin -5-yl ! (3r, 5s) -3, 5-dihydroxyhept-6-enoic acid and crystalline intermediates thereof
WO2005063728A2 (en) 2003-12-24 2005-07-14 Teva Pharmaceutical Industries Ltd. Process for preparation of statins with high syn to anti ratio
US20060004200A1 (en) 2004-06-21 2006-01-05 Srinivasulu Gudipati Processes to produce intermediates for rosuvastatin
WO2006067456A2 (en) 2004-12-24 2006-06-29 Astrazeneca Uk Limited Process for preparing rosuvastatin

Non-Patent Citations (35)

* Cited by examiner, † Cited by third party
Title
Barry et al. (1982) Easy and Efficient Anion Alkylations In Solid-Liquid PTC Conditions, Tetrahedron Lett. 23(51):5407-5408.
Barry et al. (1983) Alkylations En Absence De Solvant Organique. Effets D'Addition D'Oxydes Mineraux Et De Sels D'Ammonium-II, Tetradron 39(16):2673-2677.
Bennett et al., "Methyl (3R)-3-Hydroxyhex -5-Enoate" Journal of the Chemical Society, Perkin Transactions 1. 1:133-140 (1991).
Bram et al. (1985) Anionic Activation by Solid-Liquid Phase Transfer Catalysis Without Solvent: An Improvement in Organic Synthesis, Israel J. Chem. 26:291-298.
Chevallet et al., Tetr. Let. 34(46):7409 (1993).
Chikara et al. (1993) Preparation of optically active 5,6-epoxyhexanoic acid esters as materials for physiologically active substances, Chemical Abstracts+ Indexes, American Chemical Society, vol. 118, No. 11, p. 832, XP002178273.
Crowther et al., Org. Synth. 51:96 (1971).
Gijsen et al. (1996) Recent Advances in the Chemoenzymatic Synthesis of Carbohydrates and Carbohydrate Mimetics, Chem. Rev. 96(1):443-473.
Greenberg et al. "Development of an efficient, scalable, aldolase-catalyzed process for enantioselective synthesis of statin intermediates" PNAS 101(16):5788-5793 (2004).
Halpern (1997) Choosing a Phase-Transfer Catalyst, Phase-Transfer Communications, 3(1):1-16.
Harris et al , Acy-CoA:cholestrol o-acyl transferase (ACAT) Inhibitors. J. Med. Chem. 1992, 35, p. 4384-4392. *
Inanaga et al., Bull. Chem. Soc. Japan 52(7):1989 (1979).
International Search Report mailed on Oct. 9, 2001, for PCT patent application No. PCT/NL01/00535, filed on Jul. 12, 2001, 4 pages.
Kaneko et al. "Preparation of optically active 5,6-epoxyhexanoic acid esters as materials for physiologically active substances" Chemical Abstracts+ Indexes, American Chemical Society, Columbus, US 118(11):832 (1993).
March, Advanced Organic Chemistry, Reactions, Mechanisms and Structure 1992, p. 392.
March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th ed., John Wiley & Sons, Inc, p. 378 (1992).
Menges et al. "Oxidative Degradation of gamma-Butyrolactons into 1,3-Diols via a Criegee Rearrangement of Peroxosulfonates. An Enantioselective Synthesis of Compactin Lactone and its Diastereomer" Synlett 12:901-905 (1993).
Menges et al. "Oxidative Degradation of γ-Butyrolactons into 1,3-Diols via a Criegee Rearrangement of Peroxosulfonates. An Enantioselective Synthesis of Compactin Lactone and its Diastereomer" Synlett 12:901-905 (1993).
Morrison and Boyd "Alkaline hydrolysis of esters" Lehrbuch der Organischen Chemie, 2nd ed., Verlag Chemie, p. 739 (1978) (Translation enclosed).
Murakami et al., Heterocycles 31(11):2055 (1990).
Murphy and Koehler, J. Org. Chem. (1970) 35(7):2429-2430.
Nebergall et al , College Chemistry with qualitative analysis, p. 89,1980. *
Phase Transfer Catalysis, Principles , And Techniques (C.M. Starks; Academic Press, 1978), pp. 140-147.
Presentation given at the 20th International Congress of Heterocyclic Chemistry in Palermo, Aug. 1-5, 2005.
Presentation given at the Gordon Conference on Heterocyclic Compounds, Salve Regina University, Newport, Rhode Island, Jul. 4-9, 2004.
Rayle and Fellmeth, Org Process R&D 3:172 (1999).
Sakaki, "Lipase Catalysed Asymetric Synthesis of 6-(3-Chloro-2-Hydroxypropyl)-1,3-Dioxin-4-Ones" Tetrahedron: Asymmetry 2(5):343-6 (1991).
Shao et al. "Asymmetric hydrogenation of 3,5-Dioxoesters catalyzed by Ru-binap complex: A short step asymmetric synthesis of 6-substituted 5,6-dihydro-2-pyrones" Tetrahedron 49(10) :1997-2010 (1993).
Takeda et al., Synthesis p. 1063 (1994).
Thierry et al., Tetr. Let. 39:1557 (1998).
Watanabe et al., Bioorg. & Med. Chem. 5(2):437-444 (1997).
Watanabe et al., Drugs of the Future 24(5):511-513 (1999).
Weibetaenfels et al., Z. Chem 12(7):264 (1972).
Weiβenfels et al., Z. Chem 12(7):264 (1972).
Ziegler and Berger, Synth. Comm. 9:539-543 (1979).

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100209984A1 (en) * 2000-05-09 2010-08-19 Astrazeneca Uk Limited Process for the preparation of dihydroxy esters and derivatives thereof
US7888083B2 (en) 2000-05-09 2011-02-15 Astrazeneca Uk Limited Process for the preparation of dihydroxy esters and derivatives thereof
US7989643B2 (en) * 2000-07-19 2011-08-02 Astrazeneca Uk Ltd. Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivatives
US20100136339A1 (en) * 2000-07-19 2010-06-03 Astrazeneca Uk Ltd. Process for the Preparation of 2-(6-Substituted-1,3-Dioxane-4-yl)Acetic Acid Derivatives
US7816528B2 (en) 2001-07-13 2010-10-19 Astrazeneca Uk Limited Preparation of aminopyrimidine compounds
US20080058520A1 (en) * 2001-07-13 2008-03-06 Akio Matsushita Preparation of Aminopyrimidine Compounds
US8614320B2 (en) 2001-07-13 2013-12-24 Astrazeneca Uk Limited Preparation of aminopyrimidine compounds
US8222412B2 (en) 2001-07-13 2012-07-17 Astrazeneca Uk Limited Preparation of aminopyrimidine compounds
US20110160455A1 (en) * 2001-07-13 2011-06-30 Astrazeneca Uk Ltd. Preparation of Aminopyrimidine Compounds
US7842807B2 (en) * 2002-08-13 2010-11-30 Astrazeneca Uk Limited Process for preparing the calcium salt of rosuvastatin
US20090286819A1 (en) * 2002-08-13 2009-11-19 Astrazeneca Ab Process for Preparing the Calcium Salt of Rosuvastatin
US20080221323A1 (en) * 2003-06-05 2008-09-11 Jeffrey Norman Crabb Production of Rosuvastatin Calcium Salt
US8063213B2 (en) 2003-06-05 2011-11-22 Astrazeneca Uk Limited Production of rosuvastatin calcium salt
US8436167B2 (en) 2003-09-10 2013-05-07 Astrazeneca Uk Limited Chemical compounds
US20070255060A1 (en) * 2003-10-24 2007-11-01 Tetsuo Okada Process for the Manufacture of the Calcium Salt of Rosuvastatin (E)-7-'4-(4-Fluorophenyl)-6-Isopropyl-2-'Methyl (Methylsulfonyl) Amino ! Pyrmidin -5-Yl! (3R, 5S)-3,5-Dihydroxyhept-6-Enoic Acid and Crystalline Intermediates Thereof
US9371291B2 (en) 2003-10-24 2016-06-21 Astrazeneca Uk Limited Process for the manufacture of the calcium salt of rosuvastatin (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl](3R,5S)-3,5-Dihydroxyhept-6-enoic acid and crystalline intermediates thereof
US8034932B2 (en) 2004-12-24 2011-10-11 Astrazeneca Uk Limited Chemical process
US20080207903A1 (en) * 2004-12-24 2008-08-28 Michael Butters Chemical Process
US20100228028A1 (en) * 2005-07-08 2010-09-09 Michael Butters Processes for the manufacture of rosuvastatin and intermediates
US20080188657A1 (en) * 2006-12-01 2008-08-07 Astrazeneca Uk Limited Chemical process

Also Published As

Publication number Publication date
IS2386B (en) 2008-07-15
CZ2003163A3 (en) 2003-05-14
KR20030040224A (en) 2003-05-22
CN100378091C (en) 2008-04-02
DE60123444T2 (en) 2007-08-23
WO2002006266A1 (en) 2002-01-24
CA2415963A1 (en) 2002-01-24
EP1317440A1 (en) 2003-06-11
KR20080078925A (en) 2008-08-28
US7989643B2 (en) 2011-08-02
SK352003A3 (en) 2003-05-02
ATE340790T1 (en) 2006-10-15
CY1105881T1 (en) 2011-02-02
NO20030025D0 (en) 2003-01-03
ES2387313T3 (en) 2012-09-20
EP1700854A1 (en) 2006-09-13
US20110251406A1 (en) 2011-10-13
IL177824A0 (en) 2006-12-31
US6870059B2 (en) 2005-03-22
NO328935B1 (en) 2010-06-21
CN101081842B (en) 2012-01-04
CN1443183A (en) 2003-09-17
CN1680363A (en) 2005-10-12
RU2266903C2 (en) 2005-12-27
PT1317440E (en) 2007-01-31
IL153980A0 (en) 2003-07-31
ZA200300478B (en) 2004-01-26
UA77944C2 (en) 2007-02-15
NZ523703A (en) 2004-08-27
SK287755B6 (en) 2011-08-04
SK287756B6 (en) 2011-08-04
DK1317440T3 (en) 2007-01-08
AU7583001A (en) 2002-01-30
JP5006499B2 (en) 2012-08-22
IS8690A (en) 2007-11-15
JP2004504315A (en) 2004-02-12
KR100865016B1 (en) 2008-10-23
HUP0303166A2 (en) 2003-12-29
MXPA03000498A (en) 2003-06-24
CZ302718B6 (en) 2011-09-21
EP1317440B1 (en) 2006-09-27
CN101081842A (en) 2007-12-05
EP1700854B1 (en) 2012-05-23
IL153980A (en) 2006-10-05
NO20030025L (en) 2003-01-03
BR0112535A (en) 2003-07-01
US20030158426A1 (en) 2003-08-21
PL207115B1 (en) 2010-11-30
IS6680A (en) 2003-01-15
JP2012111757A (en) 2012-06-14
HUP0303166A3 (en) 2005-11-28
US20100136339A1 (en) 2010-06-03
HK1097260A1 (en) 2007-06-22
KR20070121063A (en) 2007-12-26
AU2001275830B2 (en) 2006-07-20
DE60123444D1 (en) 2006-11-09
CA2415963C (en) 2008-02-26
PL359332A1 (en) 2004-08-23
US20050148785A1 (en) 2005-07-07
NL1015744C2 (en) 2002-01-22
EE200300024A (en) 2004-10-15
ES2272506T3 (en) 2007-05-01

Similar Documents

Publication Publication Date Title
US7642363B2 (en) Process for the preparation of 2-(6-substituted-1,3-dioxane-4-YL) acetic acid derivatives
AU2001275830A1 (en) Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivatives
SK143793A3 (en) The enzymatic process for the stereoselective preparation of a heterobicyclic alcohol enantiomer
AU2006203127B2 (en) Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl) acetic acid derivatives
EP1620423A1 (en) Process for the preparation of (4-hydroxy-6-oxo-tetrahydropyran-2-yl) acetonitrile and derivatives thereof
HK1097260B (en) Intermediates for the preparation of 2-(6-substituted-1,3-dioxane-4-yl) acetic acid derivatives
HK1059261A (en) Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivatives
US6028213A (en) Optically active cis-1,3-cyclohexanedicarboxylic acid monoesters with high enantiomeric purity and process for their preparation
HU213569B (en) Enzymatic process for the stereoselective preparation of a heterobicyclic alcohol enantiomer

Legal Events

Date Code Title Description
STCF Information on status: patent grant

Free format text: PATENTED CASE

FPAY Fee payment

Year of fee payment: 4

FPAY Fee payment

Year of fee payment: 8

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 12TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1553); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Year of fee payment: 12